Synthesis and preliminary assessment of the anticancer and Wnt/β-catenin inhibitory activity of small amide libraries of fenamates and profens

As part of an ongoing program to study the anticancer activity of non-steroidal anti-inflammatory drugs (NSAIDs) through generating diversity libraries of multiple NSAID scaffolds, we synthesized a series of NSAID amide derivatives and screened these sets against three cancer cell lines (prostate, colon and breast) and Wnt/β-catenin signaling. The evaluated amide analog libraries show significant anticancer activity/cell proliferation inhibition, and specific members of the sets show inhibition of Wnt/β-catenin signaling.</p

Unlearning and patient safety

This chapter adds to the growing body of literature on unlearning by contributing a model applicable to the context of professional organisations, and more specifically to healthcare and patient safety. An overview of the global patient safety agenda is described and a gap in implementing sustained safety improvement identified. The UK’s efforts to bridge this gap in patient safety by transforming their NHS into a ‘learning organisation’ are discussed. The unlearning literature is reviewed and an updated model of unlearning conceptualized that contains three dimensions relevant to the study of professionals: cognitive, cultural and political. As a research agenda, this chapter provides a starting point for thinking about how unlearning can be studied in organisations; establishing a theoretical foundation for future study

HECTD2, a candidate susceptibility gene for Alzheimer's disease on 10q

Background: Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised by the deposition of amyloid plaques and neurofibrillary tangles in the brain and is the major cause of dementia. Multiple genetic loci, including 10q, have been implicated in LOAD but to date, with the exception of APOE, the underlying genes have not been identified. HECTD2 maps to 10q and has been implicated in susceptibility to human prion diseases which are also neurodegenerative conditions associated with accumulation of misfolded host proteins. In this study we test whether the HECTD2 susceptibility allele seen in prion disease is also implicated in LOAD.Methods: DNA from 320 individuals with Alzheimer's disease and 601 controls were genotyped for a HECTD2 intronic tagging SNP, rs12249854 (A/T). Groups were further analysed following stratification by APOE genotype.Results: The rs12249854 minor allele (A) frequency was higher (5.8%) in the Alzheimer's disease group as compared to the controls (3.9%), however, this was not statistically significant (P = 0.0668). No significant difference was seen in minor allele frequency in the presence or absence of the APOE epsilon 4 allele.Conclusion: The common haplotypes of HECTD2, tagged by rs12249854, are not associated with susceptibility to LOAD

Exploring types of focused factories in hospital care: a multiple case study

Background: Focusing on specific treatments or diseases is proposed as a way to increase the efficiency of hospital care. The definition of "focus" or "focused factory", however, lacks clarity. Examples in health care literature relate to very different organizations.\ud Our aim was to explore the application of the focused factory concept in hospital care, including an indication of its performance, resulting in a conceptual framework that can be helpful in further identifying different types of focused factories. Thus contributing to the understanding of the diversity of examples found in the literature. - \ud \ud Methods: We conducted a cross-case comparison of four multiple-case studies into hospital care. To cover a broad array of focus, different specialty fields were selected. Each study investigated the organizational context, the degree of focus, and the operational performance. Focus was measured using an instrument translated from industry. Data were collected using both qualitative and quantitative methods and included site visits. A descriptive analysis was performed at the case study and cross-case studies level. - \ud \ud Results: The operational performance per specialty field varied considerably, even when cases showed comparable degrees of focus. Cross-case comparison showed three focus domains. The product domain considered specialty based focused factories that treated patients for a single-specialty, but did not pursue a specific strategy nor adapted work-designs or layouts. The process domain considered delivery based focused factories that treated multiple groups of patients and often pursued strategies to improve efficiency and timeliness and adapted work-designs and physical layouts to minimize delays. The product-process domain considered procedure based focused factories that treated a single well-defined group of patients offering one type of treatment. The strategic focusing decisions and the design of the care delivery system appeared especially important for delivery and procedure based focused factories. - \ud \ud Conclusions: Focus in hospital care relates to limitations on the patient group treated and the range of services offered. Based on these two dimensions, we identified three types of focused factories: specialty based, delivery based, and procedure based. Focus could lead to better operational performance, but only when clear strategic focusing decisions are made

High Levels of Sediment Contamination Have Little Influence on Estuarine Beach Fish Communities

While contaminants are predicted to have measurable impacts on fish assemblages, studies have rarely assessed this potential in the context of natural variability in physico-chemical conditions within and between estuaries. We investigated links between the distribution of sediment contamination (metals and PAHs), physico-chemical variables (pH, salinity, temperature, turbidity) and beach fish assemblages in estuarine environments. Fish communities were sampled using a beach seine within the inner and outer zones of six estuaries that were either heavily modified or relatively unmodified by urbanization and industrial activity. All sampling was replicated over two years with two periods sampled each year. Shannon diversity, biomass and abundance were all significantly higher in the inner zone of estuaries while fish were larger on average in the outer zone. Strong differences in community composition were also detected between the inner and outer zones. Few differences were detected between fish assemblages in heavily modified versus relatively unmodified estuaries despite high concentrations of sediment contaminants in the inner zones of modified estuaries that exceeded recognized sediment quality guidelines. Trends in species distributions, community composition, abundance, Shannon diversity, and average fish weight were strongly correlated to physico-chemical variables and showed a weaker relationship to sediment metal contamination. Sediment PAH concentrations were not significantly related to the fish assemblage. These findings suggest that variation in some physico-chemical factors (salinity, temperature, pH) or variables that co-vary with these factors (e.g., wave activity or grain size) have a much greater influence on this fish assemblage than anthropogenic stressors such as contamination

Nutritional therapies for mental disorders

According to the Diagnostic and Statistical Manual of Mental Disorders, 4 out of the 10 leading causes of disability in the US and other developed countries are mental disorders. Major depression, bipolar disorder, schizophrenia, and obsessive compulsive disorder (OCD) are among the most common mental disorders that currently plague numerous countries and have varying incidence rates from 26 percent in America to 4 percent in China. Though some of this difference may be attributable to the manner in which individual healthcare providers diagnose mental disorders, this noticeable distribution can be also explained by studies which show that a lack of certain dietary nutrients contribute to the development of mental disorders. Notably, essential vitamins, minerals, and omega-3 fatty acids are often deficient in the general population in America and other developed countries; and are exceptionally deficient in patients suffering from mental disorders. Studies have shown that daily supplements of vital nutrients often effectively reduce patients' symptoms. Supplements that contain amino acids also reduce symptoms, because they are converted to neurotransmitters that alleviate depression and other mental disorders. Based on emerging scientific evidence, this form of nutritional supplement treatment may be appropriate for controlling major depression, bipolar disorder, schizophrenia and anxiety disorders, eating disorders, attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), addiction, and autism. The aim of this manuscript is to emphasize which dietary supplements can aid the treatment of the four most common mental disorders currently affecting America and other developed countries: major depression, bipolar disorder, schizophrenia, and obsessive compulsive disorder (OCD)

Neonatal Handling Affects Durably Bonding and Social Development

The neonatal period in humans and in most mammals is characterized by intense mother-young interactions favoring pair bonding and the adaptation of neonates to their new environment. However, in many post-delivery procedures, human babies commonly experience combined maternal separation and intense handling for about one hour post-birth. Currently, the effects of such disturbances on later attachment and on the development of newborns are still debated: clearly, further investigations are required. As animals present good models for controlled experimentation, we chose domestic horses to investigate this issue. Horses, like humans, are characterized by single births, long lactating periods and selective mother-infant bonds. Routine postnatal procedures for foals, as for human babies, also involve intense handling and maternal separation. In the present study, we monitored the behavior of foals from early stages of development to “adolescence”, in a normal ecological context (social groups with adults and peers). Experimental foals, separated from their mothers and handled for only 1 hour post-birth, were compared to control foals, left undisturbed after birth. Our results revealed short- and long-term effects of this unique neonatal experience on attachment and subsequent social competences. Thus, experimental foals presented patterns of insecure attachment to their mothers (strong dependence on their mothers, little play) and impaired social competences (social withdrawal, aggressiveness) at all ages. We discuss these results in terms of mother-young interactions, timing of interactions and relationships between bonding and subsequent social competences. Our results indicate that this ungulate species could become an interesting animal model. To our knowledge, this is the first clear demonstration that intervention just after birth affects bonding and subsequent social competences (at least until “adolescence”). It opens new research directions for studies on both humans and other animals

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Spatial and temporal patterns of root distribution in developing stands of four woody crop species grown with drip irrigation and fertilization.

Abstract In forest trees, roots mediate such significant carbon fluxes as primary production and soil C02 efflux. Despite the central role of roots in these critical processes, information on root distribution during stand establishment is limited, yet must be described to accurately predict how various forest types, which are growing with a range of resource limitations, might respond to environmental change. This study reports root length density and biomass development in young stands of eastern cottonwood (Populus deltoidies Bartr.) and American sycamore (Platanus occidentalis L.) that have narrow, high resource site requirements, and compares them with sweetgum (Liquidambar styraczj7ua L.) and loblolly pine (Pinus taeda L.), which have more robust site requirements. Fine roots (5 mm) were sampled to determine spatial distribu-tion in response to fertilizer and irrigation treatments delivered through drip irrigation tubes. Root length density and biomass were predominately controlled by stand development, depth and proximity to drip tubes. After accounting for this spatial and temporal variation, there was a significant increase in RLD with fertilization and irrigation for all genotypes. The response to fertilization was greater than that of irrigation. Both fine and coarse roots responded positively to resources delivered through the drip tube, indicating a wholeroot- system response to resource enrichment and not just a feeder root response. The plastic response to drip tube water and nutrient enrichment demonstmte the capability of root systems to respond to supply heterogeneity by increasing acquisition surface. Fineroot biomass, root density and specific root length were greater for broadleaved species than pine. Roots of all genotypes explored the rooting volume within 2 years, but this occurred faster and to higher root length densities in broadleaved species, indicating they had greater initial opportunity for resource acquisition than pine. Sweetgum's root characteristics and its response to resource availability were similar to the other broadleaved species, despite its hnctional resemblance to pine regarding robust site requirements. It was concluded that genotypes, irrigation arid fertilization significantly influenced tree root system development, which varied spatially in response to resource-supply heterogeneity created by dnp tubes. Knowledge of spatial and temporal patterns of root distribution in these stands will be used to interpret nutrient acquisition and soil respiration measurements